Rheumatoid Arthritis Risk Loci Research Articles

Transmembrane Protein 187 (TMEM187) and Interleukin 1 Receptor Associated Kinase (IRAK1) gene polymorphism association with rheumatoid arthritis susceptibility in Egyptian patients

Rheumatoid arthritis (RA) is a chronic auto-inflammatory disease of connective tissue with progressive joint damage and systemic disorders. RA is considered a multifactorial disease triggered by a genetic predisposition and environmental factors. Polymorphisms have been identified in the Xq28 locus as risk loci for RA. The aim of study was to assess the association between two polymorphisms in the Xq28 region containing Transmembrane Protein 187 (TMEM187) gene (rs13397) and interleukin1 receptor associated kinase (IRAK1) gene (rs1059703) with the disease susceptibility and activity in Egyptian RA patients. This study was conducted on 100 RA patients and 100 age and sex matched normal controls, together were recruited from the Rheumatology Department, Beni-Suef University Hospital. We detected TMEM187 (rs13397) and IRAK1 (rs1059703) gene polymorphisms using the real time PCR TaqMan allelic discrimination assays. We found that the frequency of the major genotypes (GG) of TMEM 187 gene was higher in RA group (54%) compared to controls (50%); while the minor genotypes (AA) was higher in the control group (22%) compared to the diseased one (18%), but such differences did not reach statistical significance (p=0.599). Regarding the IRAK1 gene, we revealed that the frequency of the major genotypes (AA) of the rs1059703 was slightly higher in RA group (48%) compared to controls (46%); while the minor genotypes (GG) was the same in both groups (26%). However, there was higher incidence of minor genotype in the TMEM187 and IRAK1 genes in males; with a statistical significance (p=0.004 and 0.015, respectively). We concluded that the major allele G of TMEM187(rs 13397) could be considered as a risk genetic allele for RA in Egyptian populations.

Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability

BackgroundGenome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These loci are shown to be enriched in immune cell-specific enhancers, but the analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, DNA accessibility, and gene expression in FLS, B cells, and T cells with genetic fine mapping of RA loci.ResultsWe identify putative causal variants, enhancers, genes, and cell types for 30–60% of RA loci and demonstrate that FLS account for up to 24% of RA heritability. TNF stimulation of FLS alters the organization of topologically associating domains, chromatin state, and the expression of putative causal genes such as TNFAIP3 and IFNAR1. Several putative causal genes constitute RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrate that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA.ConclusionOverall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.

Association of a Functional Single Nucleotide Polymorphism (rs874040) in the RBPJ Gene with Susceptibility to Rheumatoid Arthritis in Iranian Population.

Background:Rheumatoid Arthritis (RA) is a progressive, heterogeneous, and common multifactorial autoimmune disease. Several Genome-Wide Association Studies (GWASs) have revealed more than 100 risk loci for RA. One of these loci is a functional single nucleotide polymorphism (rs874040; G>C) near the recombination signal-binding protein for the immunoglobulin kappa J region (RBPJ) gene. RBPJ can convert into a transcriptional activator upon activation of the canonical Notch pathway. Notch signaling has recently emerged as an important regulator of immune responses in inflammation and autoimmune diseases. In the present study, the possible association between SNP rs874040 (G>C) upstream of the RBPJ gene with RA risk was assessed in Iranian population.Methods:A case-control study including 60 RA patients and 44 control subjects was conducted to estimate rs874040 genotypes using real-time polymerase chain reaction High Resolution Melting (HRM) method.Results:Logistic regression analysis indicated that homozygous CC and heterozygous GC genotypes increase the risk of RA compared with GG genotype (CC vs. GG; OR=11.36; 95% CI [3.93–33.33] and CG vs. GG; OR=3.78; 95% CI [1.30–10. 98]). Besides, subjects with C allele were more frequently affected with RA than subjects with G allele (OR=10.42; 95% CI [5.21–20.83]). Furthermore, in the patient group, a significant correlation was found between C-reactive protein concentrations and rs874040 polymorphism (p<0.05).Conclusion:Our findings propose a substantial correlation between rs874040 polymorphism and RA risk in Iranian population.

Identification of new susceptibility loci associated with rheumatoid arthritis

ObjectivesThe present study aimed to discover novel susceptibility loci associated with risk of rheumatoid arthritis (RA).MethodsWe performed a new genome-wide association study (GWAS) in Chinese subjects (1027 RA cases and...

Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis

ObjectivesSynovial fibroblasts (SFs) are one of the major components of the inflamed synovium in rheumatoid arthritis (RA). We aimed to gain insight into the pathogenic mechanisms of SFs through elucidating...

O11 Lymphocyte DNA methylation mediates genetic risk at RA risk loci that are shared with other immune mediated diseases

Abstract Background The aetiology of rheumatoid arthritis (RA) is complex. In particular, the vast majority of disease-associated variants implicated by genome-wide association studies are non-coding, leaving genetic mechanisms of adaptive immune dysregulation unresolved. The contribution to this process of epigenetic factors, including the addition of methyl groups to DNA, also remains uncertain. To address these issues and prioritise causal genes for downstream study, genome-wide data incorporating DNA methylation and gene expression measurements from lymphocyte subsets in an early arthritis inception cohort, were available. Methods Whole genome methylation and transcription data from isolated CD4+ T cells and B cells of &amp;gt; 100 well-characterised inflammatory arthritis patients, all of whom were naïve to immunomodulatory treatments and of Northern European ancestry, were obtained (Illumina HumanHT-12 v4 Expression BeadChip and Infinium MethylationEPIC BeadChip arrays, respectively). Genotyping was undertaken using the Illumina Human CoreExome-24 version 1-0 array. After independent pre-processing, normalisation and quality control of paired CD4+ and B lymphocyte data, methylation quantitative trait loci (meQTLs) were first modelled using the MatrixEQTL package in each cell type. Next, at RA risk-associated cis-CpGs, correlations between site-specific methylation and the expression of genes within ±500Kb identified quantitative trait methylations (eQTMs). To infer directionality of SNP-CpG-transcript associations a causal inference test (CIT) was applied. Multiple testing was accounted for, and in vitro assays were used to validate meQTLs at loci of interest and confirm regulatory mechanisms. Further analysis integrated GWAS data from other immune mediated diseases (IMDs) and additional publically available resources. Results We found strong evidence that disease-associated DNA variants regulate cis-CpG methylation of DNA in CD4+ T and/or B cells at 37% RA loci. In general we observed these variants to preferentially modify methylation at sites mapping to lymphocyte enhancers and regions flanking transcription start sites, and at positions bound by the NFκB transcription factor. Using paired, cell-specific transcriptomic data and a statistical approach to infer causality, we then identified examples where site-specific DNA methylation in turn mediates gene expression, including ORMDL3/GSDMB, IL6ST/ANKRD55, FCRL3 and JAZF1 in CD4+ lymphocytes. Leveraging GWAS data we noted that a number of genes regulated in this way highlight mechanisms common to RA, multiple sclerosis and asthma, distinguishing these IMDs from osteoarthritis which is considered a primarily degenerative disease. To validate our findings, cis-meQTL effects at sentinel loci were replicated by pyrosequencing in an independent cohort of genotyped early arthritis patients, and methylation-mediated regulation of FCRL3 expression downstream of the regulatory SNP was confirmed experimentally using a luciferase reporter assay in Jurkat T-cells. Conclusion Our observations highlight important mechanisms of genetic risk in RA and the wider context of autoimmunity. They confirm the utility of DNA methylation profiling as a tool for causal gene prioritisation and, potentially, therapeutic targeting in complex IMD. Disclosures A.D. Clark None. N. Nair None. A.E. Anderson None. N. Thalayasingam None. N. Naamane None. A.J. Skelton None. J. Diboll None. A. Barton None. S. Eyre None. J.D. Isaacs None. L.N. Reynard None. A.G. Pratt Grants/research support; I am a recipient of an unrestricted, investigator initiated research grant from Pfizer, paid to Newcastle University.

Rheumatoid Arthritis Patients, Both Newly Diagnosed and Methotrexate Treated, Show More DNA Methylation Differences in CD4+ Memory Than in CD4+ Naïve T Cells.

Background: Differences in DNA methylation have been reported in B and T lymphocyte populations, including CD4+ T cells, isolated from rheumatoid arthritis (RA) patients when compared to healthy controls. CD4+ T cells are a heterogeneous cell type with subpopulations displaying distinct DNA methylation patterns. In this study, we investigated DNA methylation using reduced representation bisulfite sequencing in two CD4+ T cell populations (CD4+ memory and naïve cells) in three groups: newly diagnosed, disease modifying antirheumatic drugs (DMARD) naïve RA patients (N = 11), methotrexate (MTX) treated RA patients (N = 18), and healthy controls (N = 9) matched for age, gender and smoking status.Results: Analyses of these data revealed significantly more differentially methylated positions (DMPs) in CD4+ memory than in CD4+ naïve T cells (904 vs. 19 DMPs) in RA patients compared to controls. The majority of DMPs (72%) identified in newly diagnosed and DMARD naïve RA patients with active disease showed increased DNA methylation (39 DMPs), whereas most DMPs (80%) identified in the MTX treated RA patients in remission displayed decreased DNA methylation (694 DMPs). Interestingly, we also found that about one third of the 101 known RA risk loci overlapped (±500 kb) with the DMPs. Notably, introns of the UBASH3A gene harbor both the lead RA risk SNP and two DMPs in CD4+ memory T cells.Conclusion: Our results suggest that RA associated DNA methylation differences vary between the two T cell subsets, but are also influenced by RA characteristics such as disease activity, disease duration and/or MTX treatment.

A novel nonsense variant in SUPT20H gene associated with Rheumatoid Arthritis identified by Whole Exome Sequencing of multiplex families.

The triggering and development of Rheumatoid Arthritis (RA) is conditioned by environmental and genetic factors. Despite the identification of more than one hundred genetic variants associated with the disease, not all the cases can be explained. Here, we performed Whole Exome Sequencing in 9 multiplex families (N = 30) to identify rare variants susceptible to play a role in the disease pathogenesis. We pre-selected 77 genes which carried rare variants with a complete segregation with RA in the studied families. Follow-up linkage and association analyses with pVAAST highlighted significant RA association of 43 genes (p-value < 0.05 after 106 permutations) and pinpointed their most likely causal variant. We re-sequenced the 10 most significant likely causal variants (p-value ≤ 3.78*10−3 after 106 permutations) in the extended pedigrees and 9 additional multiplex families (N = 110). Only one SNV in SUPT20H: c.73A>T (p.Lys25*), presented a complete segregation with RA in an extended pedigree with early-onset cases. In summary, we identified in this study a new variant associated with RA in SUPT20H gene. This gene belongs to several biological pathways like macro-autophagy and monocyte/macrophage differentiation, which contribute to RA pathogenesis. In addition, these results showed that analyzing rare variants using a family-based approach is a strategy that allows to identify RA risk loci, even with a small dataset.

Genetic influences on susceptibility to rheumatoid arthritis in African-Americans

Large meta-analyses of rheumatoid arthritis (RA) susceptibility in European (EUR) and East Asian (EAS) populations have identified >100 RA risk loci, but genome-wide studies of RA in African-Americans (AAs) are absent. To address this disparity, we performed an analysis of 916 AA RA patients and 1392 controls and aggregated our data with genotyping data from >100000 EUR and Asian RA patients and controls. We identified two novel risk loci that appear to be specific to AAs: GPC5 and RBFOX1 (PAA<5×10-9). Most RA risk loci are shared across different ethnicities, but among discordant loci, we observed strong enrichment of variants having large effect sizes. We found strong evidence of effect concordance for only 3 of the 21 largest effect index variants in EURs. We used the trans-ethnic fine-mapping algorithm PAINTOR3 to prioritize risk variants in >90 RA risk loci. Addition of AA data to those of EUR and EAS descent enabled identification of seven novel high-confidence candidate pathogenic variants (defined by posterior probability>0.8). In summary, our trans-ethnic analyses are the first to include AAs, identified several new RA risk loci and point to candidate pathogenic variants that may underlie this common autoimmune disease. These findings may lead to better ways to diagnose or stratify treatment approaches in RA.

Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis.

ObjectiveJuvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)–positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF‐positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies.MethodsPatients with RF‐positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single‐nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF‐positive polyarticular JIA.ResultsAs expected, the HLA region was strongly associated with RF‐positive polyarticular JIA (P = 5.51 × 10−31). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF‐negative polyarticular JIA risk loci were associated with RF‐positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF‐positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF‐negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF‐positive polyarticular JIA was more similar to that of RA patients with age at onset 16–29 years than to that of RA patients with age at onset ≥70 years.Conclusion RF‐positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood‐onset presentation of autoantibody‐positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies.

CD4+ and B Lymphocyte Expression Quantitative Traits at Rheumatoid Arthritis Risk Loci in Patients With Untreated Early Arthritis: Implications for Causal Gene Identification.

ObjectiveRheumatoid arthritis (RA) is a genetically complex disease of immune dysregulation. This study sought to gain further insight into the genetic risk mechanisms of RA by conducting an expression quantitative trait locus (eQTL) analysis of confirmed genetic risk loci in CD4+ T cells and B cells from carefully phenotyped patients with early arthritis who were naive to therapeutic immunomodulation.Methods RNA and DNA were isolated from purified B and/or CD4+ T cells obtained from the peripheral blood of 344 patients with early arthritis. Genotyping and global gene expression measurements were carried out using Illumina BeadChip microarrays. Variants in linkage disequilibrium (LD) with non‐HLA RA single‐nucleotide polymorphisms (defined as r2 ≥ 0.8) were analyzed, seeking evidence of cis‐ or trans‐eQTLs according to whether the associated probes were or were not within 4 Mb of these LD blocks.ResultsGenes subject to cis‐eQTL effects that were common to both CD4+ and B lymphocytes at RA risk loci were FADS1,FADS2,BLK,FCRL3,ORMDL3,PPIL3, and GSDMB. In contrast, those acting on METTL21B,JAZF1,IKZF3, and PADI4 were unique to CD4+ lymphocytes, with the latter candidate risk gene being identified for the first time in this cell subset. B lymphocyte–specific eQTLs for SYNGR1 and CD83 were also found. At the 8p23 BLK–FAM167A locus, adjacent genes were subject to eQTLs whose activity differed markedly between cell types; in particular, the FAM167A effect displayed striking B lymphocyte specificity. No trans‐eQTLs approached experiment‐wide significance, and linear modeling did not identify a significant influence of biologic covariates on cis‐eQTL effect sizes.ConclusionThese findings further refine the understanding of candidate causal genes in RA pathogenesis, thus providing an important platform from which downstream functional studies, directed toward particular cell types, may be prioritized.

A Multinational Arab Genome-Wide Association Study Identifies New Genetic Associations for Rheumatoid Arthritis.

Genetic factors underlying susceptibility to rheumatoid arthritis (RA) in Arab populations are largely unknown. This genome-wide association study (GWAS) was undertaken to explore the generalizability of previously reported RA loci to Arab subjects and to discover new Arab-specific genetic loci. The Genetics of Rheumatoid Arthritis in Some Arab States Study was designed to examine the genetics and clinical features of RA patients from Jordan, the Kingdom of Saudi Arabia, Lebanon, Qatar, and the United Arab Emirates. In total, >7 million single-nucleotide polymorphisms (SNPs) were tested for association with RA overall and with seropositive or seronegative RA in 511 RA cases and 352 healthy controls. In addition, replication of 15 signals was attempted in 283 RA cases and 221 healthy controls. A genetic risk score of 68 known RA SNPs was also examined in this study population. Three loci (HLA region, intergenic 5q13, and 17p13 at SMTNL2/GGT6) reached genome-wide significance in the analyses of association with RA and with seropositive RA, and for all 3 loci, evidence of independent replication was demonstrated. Consistent with the findings in European and East Asian populations, the association of RA with HLA-DRB1 amino acid position 11 conferred the strongest effect (P = 4.8 × 10-16 ), and a weighted genetic risk score of previously associated RA loci was found to be associated with RA (P = 3.41 × 10-5 ) and with seropositive RA (P = 1.48 × 10-6 ) in this population. In addition, 2 novel associations specific to Arab populations were found at the 5q13 and 17p13 loci. This first RA GWAS in Arab populations confirms that established HLA-region and known RA risk alleles contribute strongly to the risk and severity of disease in some Arab groups, suggesting that the genetic architecture of RA is similar across ethnic groups. Moreover, this study identified 2 novel RA risk loci in Arabs, offering further population-specific insights into the pathophysiology of RA.

TMEM187-IRAK1 Polymorphisms Associated with Rheumatoid Arthritis Susceptibility in Tunisian and French Female Populations: Influence of Geographic Origin.

Polymorphisms have been identified in the Xq28 locus as risk loci for rheumatoid arthritis (RA). Here, we investigated the association between three polymorphisms in the Xq28 region containing TMEM187 and IRAK1 (rs13397, rs1059703, and rs1059702) in two unstudied populations: Tunisian and French. The rs13397 G and rs1059703 T major alleles were significantly increased in RA patients (n = 408) compared with age-matched controls (n = 471) in both Tunisian and French women. These results were confirmed by a meta-analysis replication study including two independent Greek and Korean cohorts. The rs1059702 C major allele was significantly associated with RA, only with French women. In the French population, the GTC haplotype displayed a protective effect against RA, while the ATC, GCC, and GTT haplotypes conferred significant risk for RA. No association for these haplotypes was found in the Tunisian population. Our results replicated for the first time the association of the three Xq28 polymorphisms with RA risk in Tunisian and French populations and suggested that RA susceptibility is associated with TMEM187-IRAK1 polymorphisms in women. Our data further support the involvement of X chromosome in RA susceptibility and evidence ethnicities differences that might be explained by differences in the frequencies of SE HLA-DRB1 alleles between both populations.

Dense Genotyping of Immune-Related Regions Identifies Loci for Rheumatoid Arthritis Risk and Damage in African Americans

More than 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody-positive RA and 933 African American controls on the Immunochip (iChip) array. Using multivariable regression, we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (odds ratio = 1.97, p = 1.28 × 10−15) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11 and TNFSF18 loci were suggestively associated (10−4 < p < 3.1 × 10−6). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants, including rs9653442, rs7608424 and rs6712515, as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1 and ETS1 — but no variants within the major histocompatibility complex — were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we used the dense genotyping of the iChip array and the unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1 and IL2RA.

A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus

ObjectivesDuring the last years, genome-wide association studies (GWASs) have identified a number of common genetic risk factors for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the genetic overlap...

Integrative genomic deconvolution of rheumatoid arthritis GWAS loci into gene and cell type associations.

BackgroundAlthough genome-wide association studies (GWAS) have identified over 100 genetic loci associated with rheumatoid arthritis (RA), our ability to translate these results into disease understanding and novel therapeutics is limited. Most RA GWAS loci reside outside of protein-coding regions and likely affect distal transcriptional enhancers. Furthermore, GWAS do not identify the cell types where the associated causal gene functions. Thus, mapping the transcriptional regulatory roles of GWAS hits and the relevant cell types will lead to better understanding of RA pathogenesis.ResultsWe combine the whole-genome sequences and blood transcription profiles of 377 RA patients and identify over 6000 unique genes with expression quantitative trait loci (eQTLs). We demonstrate the quality of the identified eQTLs through comparison to non-RA individuals. We integrate the eQTLs with immune cell epigenome maps, RA GWAS risk loci, and adjustment for linkage disequilibrium to propose target genes of immune cell enhancers that overlap RA risk loci. We examine 20 immune cell epigenomes and perform a focused analysis on primary monocytes, B cells, and T cells.ConclusionsWe highlight cell-specific gene associations with relevance to RA pathogenesis including the identification of FCGR2B in B cells as possessing both intragenic and enhancer regulatory GWAS hits. We show that our RA patient cohort derived eQTL network is more informative for studying RA than that from a healthy cohort. While not experimentally validated here, the reported eQTLs and cell type-specific RA risk associations can prioritize future experiments with the goal of elucidating the regulatory mechanisms behind genetic risk associations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-0948-6) contains supplementary material, which is available to authorized users.

From the era of genome analysis to the era of genomic drug discovery: a pioneering example of rheumatoid arthritis.

Although we have obtained comprehensive catalogs of genetic risk loci that are linked to human diseases, little is known regarding how to devise a systematic strategy to integrate genetic study results with diverse biological resources. Such strategies will be crucial for providing novel insights into disease biology and for aiding drug discovery as an ultimate goal. Here we describe the current progress in this field using a pioneering example of large-scale genetic association studies on rheumatoid arthritis (RA), an autoimmune disease characterized by inflammation and destruction of joints. Through functional and bioinformatic annotations of risk single nucleotide polymorphisms (SNPs) and genes from >100 RA risk loci identified by genome-wide association study (GWAS) meta-analysis, we found novel biological insights into RA pathogenicity. Further, by integrating RA genetic findings with the complete catalog of approved drugs for RA and other diseases, we provide empirical data to indicate that human genetic-based approaches may be useful for supporting 'genetics-driven genomic drug discovery' efforts in complex human traits and suggest that further development of integrative approaches should be undertaken.

THU0515 C5orf30 A Novel Regulator of Tissue Damage in Rheumatoid Arthritis

BackgroundA recent genome wide association study identified the variant rs26232 in the first intron of the uncharacterized gene, C5orf30, as a rheumatoid arthritis (RA) susceptibility variant1. In addition, it has...

Novel risk loci for rheumatoid arthritis in Han Chinese and congruence with risk variants in Europeans.

To investigate differences in genetic risk factors for rheumatoid arthritis (RA) in Han Chinese as compared with Europeans. A genome-wide association study was conducted in China with 952 patients and 943 controls, and 32 variants were followed up in 2,132 patients and 2,553 controls. A transpopulation meta-analysis with results from a large European RA study was also performed to compare the genetic architecture across the 2 ethnic remote populations. Three non-major histocompatibility complex (non-MHC) loci were identified at the genome-wide significance level, the effect sizes of which were larger in anti-citrullinated protein antibody (ACPA)-positive patients than in ACPA-negative patients. These included 2 novel variants, rs12617656, located in an intron of DPP4 (odds ratio [OR] 1.56, P = 1.6 × 10(-21) ), and rs12379034, located in the coding region of CDK5RAP2 (OR 1.49, P = 1.1 × 10(-16) ), as well as a variant at the known CCR6 locus, rs1854853 (OR 0.71, P = 6.5 × 10(-15) ). The analysis of ACPA-positive patients versus ACPA-negative patients revealed that rs12617656 at the DPP4 locus showed a strong interaction effect with ACPAs (P = 5.3 × 10(-18) ), and such an interaction was also observed for rs7748270 at the MHC locus (P = 5.9 × 10(-8) ). The transpopulation meta-analysis showed genome-wide overlap and enrichment in association signals across the 2 populations, as confirmed by prediction analysis. This study has expanded the list of alleles that confer risk of RA, provided new insight into the pathogenesis of RA, and added empirical evidence to the emerging polygenic nature of complex trait variation driven by common genetic variants.

High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci

A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45,790 European case-control samples. We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.